Voluntary wheel running reduces infarct size through thioredoxin-1 and survival pathways.

Ischemic heart disease remains the leading cause of mortality worldwide, and exercise is recognized as one of the most effective non-pharmacological strategies for cardioprotection. Voluntary wheel running in mice is an established experimental model that induces systemic and cardiac adaptations, yet the molecular mediators underlying exercise-induced cardioprotection remain incompletely understood. In this study, we investigated the role of thioredoxin-1 (Trx1), a potent intracellular antioxidant, in the cardioprotective effects of exercise. Mice underwent four weeks of voluntary wheel running, achieving an average distance of approximately 7 km per day. Exercised wild-type mice exhibited reduced infarct size following ischemia/reperfusion injury, along with physiological adaptations such as increased heart and skeletal muscle mass and improved autonomic regulation. In contrast, mice expressing inactive Trx1 failed to benefit from exercise, showing no reduction in infarct size compared with sedentary controls. These findings demonstrate that functional Trx1 is required for exercise-induced myocardial protection and is associated with the activation of prosurvival signaling pathways. Understanding the interplay between Trx1 and exercise may provide new insight into the mechanisms of cardioprotection and help guide the development of cost-effective, non-invasive strategies for the prevention and treatment of ischemic heart disease.